Cellular Basis for Estrogen Effects in the RVLM

绝经后，血压和心血管风险增加。在外周，性腺类固醇通过基因组[通过核雌激素、孕激素和雄激素受体(ER、PR和AR)]和非基因组(通过膜ER、PR和AR)机制来影响肾素-血管紧张素系统(RAS)的功能，从而参与心血管调节。这些效应可能涉及血管紧张素-1(AT1)受体的数目或质膜靶向性的改变，或AT1受体相关的信号机制的改变，包括NAD(P)H氧化酶。同样，在中枢神经系统，性腺激素可能通过影响延髓头端腹外侧区(RVLM)的血管紧张素II(Ang II)活动而影响心血管功能，RVLM是控制动脉压的关键区域。RVLM中性腺类固醇与RAS的相互作用 可能是选择性的，因为这些神经元：(A)含有核ER-α和AT1受体，以及(B)由Ang II兴奋。然而，核外ER、PR和ARs是否存在于RVLMC1球脊髓神经元或它们的传入上尚不清楚。我们的中心假设是雌激素、孕激素和雄激素部分地通过改变RVLMC1球脊髓神经元的兴奋性和Ang II反应来不同地调节中枢血压调节，并且这些影响涉及基因组和非基因组机制。我们将研究：(1)ER、PR和ARs是否对RVLM中与中枢心血管调节有关的神经元回路产生基因组和/或非基因组效应；(2)雌激素、孕激素和雄激素影响C1球脊髓神经元的功能，包括它们对Ang II和谷氨酸的反应； (3)性腺激素影响C1神经元AT1受体和NAD(P)H氧化酶亚基的膜靶向性。这些研究将在正常雌性大鼠、Ang II诱导的高血压雌性大鼠和ER“敲除”雌性小鼠中进行。将使用光镜和电子显微镜免疫细胞化学的方法，辅以膜片钳记录和单细胞逆转录聚合酶链式反应。更好地了解不同性别的血压调节将有助于设计更有效的绝经后心血管疾病治疗策略。

After menopause, blood pressure and cardiovascular risk increases. In the periphery, gonadal steroids contribute to cardiovascular regulation by influencing the function of the renin-angiotensin system (RAS) through genomic [via nuclear estrogen, progesterone and androgen receptors (ERs, PRs and ARs)] and non-genomic (via membrane ERs, PRs and ARs) mechanisms. These effects may involve alterations in the number or plasrnalemmal targeting of angiotensin 1 (AT1) receptors, or in AT1 receptor-linked signaling mechanisms, including NAD(P)H oxidase. Similarly, in the CNS, gonadal steroids may influence cardiovascular function by affecting angiotensin II (Ang II) actions in the rostral ventrolateral medulla (RVLM), an area crucial for the control of arterial pressure. Gonadal steroid-RAS interactions in the RVLM may be selective for the C1 adrenergic subset of bulbospinal neurons since these neurons: (a) contain nuclear ER-alpha and AT1 receptors, and (b) are excited by Ang II. It is not known, however, whether extranuclear ERs, PRs and ARs are present and functional on RVLM C1 bulbospinal neurons or their afferents. Our central hypothesis is that estrogens, progestins and androgens differentially modulate central blood pressure regulation, in part by altering the excitability and Ang II responses of RVLM C1 bulbospinal neurons, and that these effects involve both genomic and non-genomic mechanisms. We will examine whether: (1) ERs, PRs and ARs are positioned to have genomic and/or non-genomic effects on neuronal circuits in the RVLM relevant to central cardiovascular regulation; (2) estrogens, progestins and androgens affect the function of C1 bulbospinal neurons including their responses to Ang II and glutamate; and (3) gonadal steroids influence the membrane targeting of AT1 receptors and NAD(P)H oxidase subunits in C1 neurons. These studies will be conducted in normal female rats, in female rats with Ang II-induced hypertension and in ER "knock-out" female mice. Light and electron microscopic immunocytochemistry of C1 neurons, complemented by patch-clamp recording and single-cell reverse transcription polymerase chain reaction, will be used. A better understanding of gender-specific blood pressure regulation will contribute to the design of more effective therapeutic strategies for post-menopausal cardiovascular disorders.